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Bisnorcymserine a butyrylcholinesterase (BuChE) inhibitor starting testing
Biff Calhoun
Posted: Sunday, January 26, 2014 9:31 AM
Joined: 8/20/2013
Posts: 56

Existing "treatment" for AD are the acetylcholinesterase inhibitor or anti-cholinesterase drugs Donepezil (Aricept), Galantamine (Razadyne), Now it looks like researcher are looking at Butyrylcholinesterase inhibitors.


 An Old study (2006)(1) reports:


AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy: primarily with acetylcholinesterase (AChE) inhibitors to amplify remaining cholinergic activity. New agents that, additionally, affect disease progression are sorely needed. Inhibition of brain butyrylcholinesterase (BuChE) represents a new drug target for AD treatment. Therefore, hand-in-hand with the development of selective ligands to inhibit BuChE in brain, it is fundamental to optimize assay conditions for kinetic studies of human BuChE. Kinetic analysis of serum BuChE, which is structurally similar to brain enzyme, was performed at dual substrate (butyrylthiocholine iodide) concentration ranges: 3-80 microM (low) and 25-800 microM (optimal) by use of the Ellman technique. Interaction of BuChE with a novel experimental AD therapeutic, bisnorcymserine (BNC; 0.06-2.0 nM) was also studied ex vivo. The IC_{50} and other key kinetic constants were determined for human serum BuChE inhibition by BNC, which proved to be a highly potent inhibitor in comparison to its structural analogue, cymserine. BNC may, additionally, lower the amyloid plaque-associated protein, amyloid-beta peptide. (1)



New Trial:


Detailed Description:

Alzheimer s disease (AD) is an irreversible, progressive brain disease that slowly impairs memory and other cognitive abilities, as well as behavior and the ability to carry out tasks. It is the most common cause of dementia among older people. Alzheimer s disease is caused by deposits of abnormal proteins throughout the brain, causing neurons to lose their ability to communicate with each other effectively, and eventually die. Communication between neurons uses chemicals called neurotransmitters that are secreted from one neuron to another across a synapse. Acetylcholine (Ach) is one of the most important neurotransmitters. Damage to the Ach (-producing) system in the brain is associated with the cognitive and functional deficits in Alzheimer's disease. Restoring this deficit in the cholinergic system is one approach to treat the symptoms of Alzheimer's disease. The action of Ach in brain is stopped/ blocked mainly by two brain enzymes called cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Inhibitors of these enzymes therefore augment the activity of surviving Ach neurons in AD. All ChEs currently approved for the treatment of AD mainly inhibit AChE and, secondarily and to a varying extent, BChE activities. Nevertheless, BChE remains a viable target in AD and potent, reversible and brain-targeted BChE inhibitors have been developed (as a class of drugs called cymserine analogs). Scientists at the NIA/NIH have developed a novel BChE inhibitor called Bisnorcymserine (BNC). Pre-clinical evidence suggest that BNC may be a safe treatment for Alzheimer s disease. Based on this, we propose this first-in-human study to evaluate the safety, tolerability and pharmacokinetics of single doses of BNC tartrate administered orally to healthy volunteers aged 55 years and older using a double-blind placebo-controlled design. The proposed doses are: 20mg, 40mg, 80mg, 160mg, 270mg and 380mg given as a single oral dose. Each dose will be tested in groups of 8 subjects. Six subjects in each cohort will receive active drug and two will receive placebo. Subjects will be kept in the unit and followed clinically and with laboratory tests for adverse effects for 32 hours; they will return for a follow-up visit to assess safety in about 7 days. A Data Safety Monitoring Board will evaluate the safety and tolerability associated with each dose level before the next higher dose is tested in a new cohort. All research will be performed at the National Institute on Aging (NIA) Clinical Research Unit located on the 5th floor of MedStar Harbor Hospital. (2)